Due to improved biotechnology, the accessibility of biologically active peptides to the pharmaceutical industry has increased considerably. However, a limiting factor in the development of peptide drugs is the relative ineffectiveness when given perorally. Almost all peptide drugs are parenterally administered, although parenterally administered peptide drugs are often connected with low patient compliance.
Exenatide is a glucagon-like peptide (GLP-1) agonist that was approved by the Food and Drug Administration for adjunctive therapy when patients with type 2 diabetes have not been optimally controlled on metformin. It is an incretin mimetic and potentiates exenatide secretion while inhibiting glucagon secretion and slowing gastric emptying.
Exenatide (marketed as Byetta) is manufactured and marketed by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide is a synthetic version of exendin-4, a hormone in the saliva of the Gila monster, a lizard native to several Southwestern American states. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, lessening the risk of hypoglycemia. Byetta is also being used by some physicians to treat insulin resistance.
Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; however, other drugs (like injectable insulin) are effective at lowering blood sugar, but can “overshoot” their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
Exenatide has a subtle yet prolonged effect to reduce appetite and thus may prevent weight gain. Most people using Exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated that the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss and the lowest 25% experience no loss or small weight gain.
Exenatide reduces liver fat content. Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice and more recently in man.
Exenatide is a polypeptide consisting of 39 amino acids with a molecular weight of 4186.6. Ex vivo human placental perfusion studies detected minimal levels on the fetal side (fetal: maternal ratio 0.017).
Exenatide is currently administered as a subcutaneous injection, generally concomitantly with a sulfonylurea or metformin. Although it has a modest effect on lowering fasting glucose levels, it markedly reduces postprandial glucose.
The present invention addresses the need for an alternate solution for administration of exenatide.